Point-of-care C-reactive protein-based tuberculosis screening among people living with HIV: planning a comparative effectiveness trial

项目摘要 异烟肼预防性治疗（IPT）是最有效和最具成本效益的干预措施，以减少 艾滋病毒感染者（PLHIV）的结核病（TB）发病率和死亡率，但由于 我们依赖于一种基于荧光素酶的筛查测试来排除活动性结核病。非洲的研究表明， 症状筛查对活动性TB的特异性较低（10-30%），不符合最低特异性 （≥70%）世界卫生组织（WHO）制定的结核病筛查要求。这种低特异性 是扩大IPT规模的主要障碍，因为如果遵循当前的结核病筛查指南， 如果没有活动性结核病，则在开始IPT之前需要进行不必要且昂贵的确证性检测。整体 该应用程序的目的是支持试验的规划活动，该试验将评估一个更 这是成功采用IPT所需的下一步。 核心假设是，基于C反应蛋白（CRP）水平的结核病筛查策略， 使用床旁（POC）检测，将改善结果并减少结核病的长期影响， 艾滋病毒/艾滋病，超越了基于艾滋病的战略。这一假设的科学前提是基于 申请人将POC CRP确定为满足最低灵敏度（≥90%）的第一个工具的工作，以及 特异性（≥70%）是WHO为结核病筛查制定的目标。该应用程序的基本原理是， 需要一年的计划期来计划一个有影响力和有效的多中心比较有效性 结核病筛查策略的试验。该提案将支持1654例随机试验的计划活动 从乌干达三个典型的艾滋病毒诊所开始抗逆转录病毒治疗的艾滋病毒感染者，随机分为两组： 筛查或基于POC CRP的TB筛查。该试验将比较开始IPT的艾滋病毒感染者比例（目的是 1)和2年患者结局（目标2）。目标2的主要终点将是一个复合终点。 终点包括累积结核病发病率和全因死亡率。Aim 2的关键次要终点 将包括单个主要终点和耐异烟肼结核病。目标3将比较成本效益 以及相对于当前建议，基于POC CRP的结核病筛查的预计流行病学影响 （症状筛查）和无筛查。这项研究是创新的，因为尽管许多试验 确定了IPT的有效性，没有试验评估了结核病筛查对IPT启动率的影响， 患者结局。此外，CRP测试将使用低成本（每次测试2美元），快速（结果3 分钟）和简单（从毛细血管血测量的水平）POC测定，增加了POC 基于CRP的结核病筛查将在最边缘的环境中实施。这项研究意义重大 因为除了量化结核病筛查的预期临床、经济和流行病学效益外， 这项工作将提供有和没有POC CRP的TB筛查有效性的明确证据， 潜在地使该领域超越作为IPT和改善患者结果的障碍的无效TB筛查。

PROJECT SUMMARY Isoniazid preventive therapy (IPT) is among the most efficacious and cost-effective interventions to reduce tuberculosis (TB) incidence and mortality among people living with HIV (PLHIV) but is grossly underutilized due to our reliance on a symptom-based screening test to rule-out active TB. Studies from Africa have shown that the symptom screen has low specificity (10-30%) for active TB and does not meet the minimum specificity (≥70%) requirement established by the World Health Organization (WHO) for TB screening. This low specificity is a major barrier to IPT scale-up because if current TB screening guidelines were followed, 70-90% of PLHIV without active TB would require unnecessary and costly confirmatory testing prior to initiating IPT. The overall objective of this application is to support planning activities for a trial that will evaluate the impact of a more effective and cost-effective TB screening strategy, which is the next step required for successful uptake of IPT. The central hypothesis is that a TB screening strategy based on C-reactive protein (CRP) levels, measured using a point-of-care (POC) assay, will improve outcomes and reduce the long-term impact of TB among PLHIV, beyond that of a symptom-based strategy. The scientific premise for this hypothesis is based on the applicant’s work that has identified POC CRP as the first tool to meet the minimum sensitivity (≥90%) and specificity (≥70%) targets established by the WHO for TB screening. The rationale for this application is that a one-year planning period is needed to plan an impactful and efficient multicenter comparative effectiveness trial of TB screening strategies. This proposal will support planning activities for an randomized trial of 1654 PLHIV initiating ART from three prototypical HIV clinics in Uganda, randomized to either symptom-based TB screening or POC CRP-based TB screening. The trial will compare the proportion of PLHIV initiating IPT (Aim 1) and two-year patient outcomes (Aim 2), by trial arm. The primary endpoint for Aim 2 will be a composite endpoint that will include cumulative TB incidence and all-cause mortality. Key secondary endpoints for Aim 2 will include individual primary endpoints and isoniazid-resistant TB. Aim 3 will compare the cost-effectiveness and projected epidemiologic impact of POC CRP-based TB screening relative to the current recommendation (symptom screening) and to no screening. This research is innovative because although numerous trials have established the effectiveness of IPT, no trial has evaluated the impact of TB screening on IPT initiation rates or patient outcomes. In addition, CRP testing will be performed using a low-cost ($2 per test), rapid (results in 3 minutes) and simple (levels measured from capillary blood) POC assay, increasing the likelihood that POC CRP-based TB screening will be implemented in even the most peripheral settings. This research is significant because in addition to quantifying the expected clinic, economic, and epidemiologic benefits of TB screening, this work will provide definitive evidence of effectiveness of TB screening with and without POC CRP, potentially moving the field beyond ineffective TB screening as a barrier to IPT and improved patient outcomes.